Sulfonylaminobenzamide compounds as anthelmintics

ABSTRACT

The present invention relates to a new compound of formula (I) wherein the variables have the meaning as indicated in the claims; or an enantiomer or salt thereof. The compounds of formula (I) are useful in the control of parasites, in particular endoparasites, in and on vertebrates.

The present invention relates to novel sulfonylaminobenzamide compoundsand their use in the control of endoparasites, for example heartworms,in warm-blooded animals.

Heartworm (Dirofilaria immitis) is a parasitic roundworm that is spreadfrom host to host through the bites of mosquitoes. The definite host isthe dog but it can also infect cats and other warm-blooded animals.Although commonly being called “heartworm” the adult worms actuallyreside in the pulmonary arterial system (lung arteries) for the mostpart, and the primary effect on the health of the animal is damage tothe lung vessels and tissue. Occasionally, adult heartworms migrate tothe right heart and even the great veins in heavy infections. Heartworminfection may result in serious disease for the host.

Heartworm infections may be combatted with arsenic-based compounds; thetreatment is time-consuming, cumbersome and often only partlysuccessful. Accordingly, the main focus is on the prevention ofheartworm infections. Heartworm prevention is currently performedexclusively by year round periodical administration of a macrocycliclactone such as ivermectin, moxidectin or milbemycin oxime to the dog,cat or else warm-blooded animal. Unfortunately, upcoming resistancy ofDirofilaria immitis against macrocyclic lactones has been observed incertain parts of the USA. Accordingly, there is a strong need forfinding new classes of compounds which are effectively controllingheartworm infections either by way of prophylaxis or by direct killingof the different stages of heartworms. It now has been foundsurprisingly that a group of novel sulfonylaminobenzamide compoundseffectively controls endoparasites including heartworms effectively onwarm-blooded animals.

SUMMARY OF THE INVENTION

The present invention therefore according to one embodiment concerns acompound of formula

or a salt or an enantiomer thereof, wherein

n is 0 or 1;

A is C₁-C₆-alkyl; C₁-C₆-haloalkyl; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; 5- or 6-membered heterocycloalkyl having from 1 to3 same or different heteroatoms selected from the group consisting of B,N, O and S, which is further unsubstituted or substituted by halogen,C₁-C₄-alkyl or C₁-C₄-alkoxy; or is phenyl which is unsubstituted orsubstituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkyl-sulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, SF₅; amino, N-mono- orN,N-di-C₁-C₆-alkylamino, tri-C₁-C₄-alkylsilyl, C₁-C₆-alkoxycarbonyl,aminocarbonyl, N-mono- or N,N-di-C₁-C₆-alkylaminocarbonyl,aminosulfonyl, N-mono- or N,N-di-C₁-C₆-alkylaminosulfonyl,C₁-C₆-alkoxycarbonylamino, N—C₁-C₄-alkyl-N—C₁-C₆-alkoxycarbonylamino,cyano, nitro, or unsubstituted or halogen-, C₁-C₄-alkyl-,C₁-C₄-haloalkyl-, C₁-C₄-alkoxy-, C₁-C₄-haloalkoxy-, amino-, cyano- ornitro-substituted C₃-C₆-heterocyclyl; or is cinnamyl, which isunsubstituted or substituted in the phenyl moiety by halogen,C₁-C₄-alkyl or C₁-C₄-alkoxy; or is a heteroaromatic radical, which isfurther unsubstituted or substituted by halogen, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₂-C₄-alkanoyl, 5- or6-membered heterocycloalkyl-C₁-C₂-alkyl or unsubstituted or halogen-,C₁-C₄-alkyl- or C₁-C₄-alkoxy-substituted phenyl; or is a hetero-bicyclicring radical comprising a total of 8 to 10 ring members, from which 1 to5, preferably 1 or 2, members are same or different heteroatoms selectedfrom the group consisting of B, N, O and S, and from which 0 to 2members are a group C(O)—, which bicyclic ring radical is furtherunsubstituted or substituted by halogen, cyano, hydroxyl, C₁-C₄-alkyl orC₁-C₄-haloalkyl;

R² is H or —S(O₂)-T;

T is C₁-C₆-alkyl, which is unsubstituted or substituted by halogen,trimethylsilyl, C₃-C₆-cycloalkyl, carboxyl or C₁-C₄-alkoxycarbonyl;C₃-C₆-cycloalkyl; C₆-C₁₂-bicarbocyclyl; phenyl which is unsubstituted orsubstituted by halogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl orC₁-C₄-alkoxy; a 5- or 6 membered heteroaromatic radical, which isfurther unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl or C₁-C₄-alkoxy; 5- or 6-memberedheterocycloalkyl having from 1 to 3 same or different heteroatomsselected from the group consisting of N, O, S and S(O₂), which isfurther unsubstituted or substituted by C₁-C₄-alkyl,C₁-C₂-alkoxycarbonyl or benzyloxycarbonyl; a group

amino; or N-mono- or N,N-di-C₁-C₄-alkylamino;

R³ is C₁-C₄-alkyl, unsubstituted or halogen-, C₁-C₄-alkyl- orC₁-C₄-haloalkyl-substituted phenyl, unsubstituted or halogen-,C₁-C₄-alkyl- or C₁-C₄-haloalkyl-substituted pyridyl,C₁-C₄-alkoxycarbonylmethyl or morpholin-4-yl-carbonylmethyl;

R⁰ is H or hydroxy; and

Y is

(i) phenyl or a phenylamino, which is substituted by one or more same ordifferent radicals selected from the group consisting of halogen;C₁-C₆-alkyl; C₁-C₆-haloalkyl; C₃-C₆-cycloalkyl; C₃-C₆-halocycloalkyl;hydroxyl; C₁-C₆-alkoxy; C₁-C₆-haloalkoxy; C₁-C₆-alkylthio;C₁-C₆-haloalkylthio; C₁-C₆-alkyl-sulfinyl; C₁-C₆-haloalkylsulfinyl;C₁-C₆-alkylsulfonyl; C₁-C₆-haloalkylsulfonyl; SF₅; amino; N-mono- orN,N-di-C₁-C₆-alkylamino; tri-C₁-C₄-alkylsilyl; C₁-C₆-alkoxycarbonyl;aminocarbonyl; N-mono- or N,N-di-C₁-C₆-alkylaminocarbonyl;aminosulfonyl; N-mono- or N,N-di-C₁-C₆-alkylaminosulfonyl;N—C₁-C₆-alkylsulfonylamino; C₁-C₆-alkoxycarbonylamino;N—C₁-C₄-alkyl-N—C₁-C₆-alkoxycarbonylamino; cyano; nitro; andunsubstituted or halogen-, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-,C₁-C₄-alkoxy-, C₁-C₄-haloalkoxy-, amino-, cyano- or nitro-substitutedC₃-C₆-heterocyclyl; or is

(ii) 5- or 6 membered heteroaryl or heteroarylamino, which is eachfurther unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl,C₂-C₄-alkanoyl, or phenyl or phenylsulfonyl which is each unsubstitutedor substituted by halogen, cyano, nitro methyl or methoxy; or is

(iii) benzoyl or 5- or 6 membered heteroarylcarbonyl, which is eachfurther unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl,C₂-C₄-alkanoyl or phenyl; or is

(iv) a C₆-C₁₂-bicarbocyclic radical; or is a

(v) a hetero-bicyclic ring radical comprising a total of 8 to 10 ringmembers, from which 1 to 5, preferably 1 or 2, members are same ordifferent heteroatoms selected from the group consisting of B, N, O andS, and from which 0 to 2 members are a group —C(O)—, which bicyclic ringradical is further unsubstituted or substituted by halogen, cyano,hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkyl or C₁-C₄-haloalkyl; or is

(vi) a radical H₂C—C(O)—NH—R⁴, wherein R⁴ is C₁-C₄-haloalkyl,C₂-C₃-alkynyl or cyano-C₁-C₄-alkyl; or

R⁰ and Y together with the N-atom to which they are attached, form apiperidinyl or piperazinyl radical which is substituted by C₁-C₄-alkyl,C₁-C₄-alkoxy, unsubstituted or halogen-, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-,amino- and/or C₁-C₄-alkoxy-substituted phenyl or benzoylamino, orunsubstituted or C₁-C₄-alkyl-, C₁-C₄-haloalkyl-, C₃-C₆-cycloalkyl- orhalogen-substituted pyridyl or pyrimidinyl;

subject to the provisos that

(i) at least one of A and Y must not be a phenyl radical if T is CH₃;and

(ii) T is C₁-C₆-alkyl which is unsubstituted or substituted as mentionedabove if A is C₁-C₆-alkyl or C₁-C₆-haloalkyl.

The invention also provides a composition comprising a compound offormula (I), or a salt or enantiomer thereof, and at least one carrier,for example a surfactant, a solid diluent and/or a liquid diluent.

In one embodiment, this invention also provides a composition forcontrolling parasites, in particular endoparasites, comprising abiologically effective amount of a compound of formula (I), or a saltthereof, and at least one additional component selected from the groupconsisting of a surfactant, a solid diluent and a liquid diluent, saidcomposition optionally further comprising a biologically effectiveamount of at least one additional pharmaceutically or veterinary activecompound or agent.

This invention also provides a method for controlling parasitescomprising contacting the parasites or their environment with apharmaceutically or veterinary effective amount of a compound of formula(I), an enantiomer or a salt thereof, (e.g., as a composition describedherein). This invention also relates to such method wherein theparasites or their environment are contacted with a compositioncomprising a pharmaceutically or veterinary effective amount of acompound of formula (I), an enantiomer or a salt thereof, and at leastone additional component selected from the group consisting of asurfactant, a solid diluent and a liquid diluent, said compositionoptionally further comprising a pharmaceutically or veterinary effectiveamount of at least one additional pharmaceutically or veterinary activecompound or agent.

This invention also provides a method for protecting an animal from aparasitic pest comprising administering to the animal a parasiticidallyeffective amount of a compound of formula (I), an enantiomer or a saltthereof.

DETAILS OF THE INVENTION

In the above recitations, the term “alkyl”, used either alone or incompound words such as “alkylthio”, “haloalkylthio”, “haloalkyl”,“N-alkylamino”, “N,N-di-alkyamino” and the like includes straight-chainor branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, n-, iso-,sec.- or tert.-butyl or the different pentyl or hexyl isomers.

The term “alkoxy” used either alone or in compound words such as“haloalkoxy”, “alkoxycarbonyl” includes, for example, methoxy, ethoxy,n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxyisomers. “Alkylthio” includes branched or straight-chain alkylthiomoieties such as methylthio, ethylthio, and the different propylthio,butylthio, pentylthio and hexylthio isomers.

“Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group.Examples of “alkylsulfinyl” include CH₃S(O)—, CH₃CH₂S(O)—,CH₃CH₂CH₂S(O)—, (CH₃)₂CHS(O)— and the different butylsulfinyl,pentylsulfinyl and hexylsulfinyl isomers.

“Alkylcarbonyl” denotes a straight-chain or branched alkyl moietiesbonded to a C(═O) moiety. Examples of “alkylcarbonyl” include CH₃C(═O)—,CH₃CH₂CH₂C(═O)— and (CH₃)₂CHC(═O)—. Examples of “alkoxycarbonyl” includeCH₃OC(═O)—, CH₃CH₂OC(═O), CH₃CH₂CH₂OC(═O)—, (CH₃)₂CHOC(═O)— and thedifferent butoxy- or pentoxycarbonyl isomers, for exampletert.-butoxycarbonyl (Boc). Examples of “alkoxycarbonylamino” includetert.-butoxycarbonylamino, examples of “N-alkoxycarbonyl” includeN-tert.-butoxycarbonyl and examples of “N-alkylamino” includeN-methylamino. Examples of “N-mono- or N,N-di-alkylaminocarbonyl”include N-methylaminocarbonyl, N-ethylaminocarbonyl,N-methyl-N-ethylaminocarbonyl, N,N-di-methylaminocarbonyl orN,N-di-ethylaminocarbonyl. Examples of “alkylcarbonylamino” includemethylcarbonylamino or ethylcarbonylamino.

Examples of “alkylsulfonyl” include CH₃S(O)₂—, CH₃CH₂S(O)₂—,CH₃CH₂CH₂S(O)₂—, (CH₃)₂CHS(O)₂—, and the different butylsulfonyl,pentylsulfonyl and hexylsulfonyl isomers. Examples of “N-mono- orN,N-di-alkylaminosulfonyl” include N-methylaminosulfonyl,N-ethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl,N,N-di-methylaminosulfonyl or N,N-di-ethylaminosulfonyl. Examples of“alkylsulfonylamino” include methylsulfonylamino or ethylsulfonylamino.

“Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. The term “alkylcycloalkyl” denotes alkyl substitution ona cycloalkyl moiety and includes, for example, ethylcyclopropyl,i-propylcyclobutyl, 3-methylcyclopentyl and 4-methycyclohexyl.

Examples of C₆-C₁₂-bicarbocyclyl are the radical of (+)- or (−)-campher(1,7,7-trimethylbicyclo[2.2.1]heptan-2-one), a radical

a radical

or indanyl.

The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different. Examples of “haloalkyl” include F₃C—, ClCH₂—, CF₃CH₂— andCF₃CCl₂—. The terms “halocycloalkyl”, “haloalkoxy”, “haloalkylthio”, andthe like, are defined analogously to the term “haloalkyl”. Examples of“haloalkoxy” include CF₃O—, CF₃CF₂—O—, CF₃CH₂O—, CCl₃CH₂O—, CF₃CHFCF₂O—and HCF₂CH₂CH₂O—. Examples of “haloalkylthio” include CCl₃S—, CF₃S—,CCl₃CH₂S— and ClCH₂CH₂CH₂S—. Examples of “haloalkylsulfinyl” includeCF₃S(O)—, CCl₃S(O)—, CF₃CH₂S(O)— and CF₃CF₂S(O)—. Examples of“haloalkylsulfonyl” include CF₃S(O)₂—, CCl₃S(O)₂—, CF₃CH₂S(O)₂— andCF₃CF₂S(O)₂—.

The total number of carbon atoms in a substituent group is indicated bythe “C_(i)-C_(j)” prefix where i and j are integers. For example, C₁-C₄alkylsulfonyl designates methylsulfonyl through butylsulfonyl.

When a compound is substituted with a substituent bearing a subscriptthat indicates the number of said substituents can exceed 1, saidsubstituents (when they exceed 1) are independently selected from thegroup of defined substituents, e.g., (R₂)_(n), n is 1 or 2.

“Aromatic” indicates that each of the ring atoms is essentially in thesame plane and has ap-orbital perpendicular to the ring plane, and inwhich (4n+2) π electrons, where n is a positive integer, are associatedwith the ring to comply with Hückel's rule.

The terms “heterocyclyl”, “heterocyclic ring” or “heterocycle” denote aring in which at least one atom forming the ring backbone is not carbon,e.g., nitrogen, oxygen sulfur or a group S(O) or S(O₂). Typically aheterocyclic ring contains no more than 4 nitrogens, no more than 2oxygens and no more than 2 sulfurs. In addition, the heterocyclic ringmay contain a group C(O)—, —S(O)— or —S(O₂)—. Unless otherwiseindicated, a heterocyclic ring can be a saturated, partiallyunsaturated, or fully unsaturated ring. When a fully unsaturatedheterocyclic ring satisfies Hückel's rule, then said ring is also calleda “heteroaromatic ring” or “heteroaryl” substituent. Unless otherwiseindicated, heterocyclic rings and ring systems can be attached throughany available carbon or nitrogen by replacement of a hydrogen on saidcarbon or nitrogen.

The term heterocyclyl, either alone or in compound words such asheterocyclyloxy may be, for example a 5- or 6-membered heterocyclicradical having from 1 to 4, preferably from 1 to 3 same or differentheteroatoms selected from the group consisting of B, N, O and S, whichis further unsubstituted or substituted. Examples of suitablesubstituents of the heterocyclyl are halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, hydroxy,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, cyano, nitro, amino, N-mono- orN,N-di-C₁-C₄-alkylamino, C₁-C₆-alkoxycarbonyl, sulfonamido, N-mono- orN,N, di-C₁-C₄-alkylsulfonamido, C₁-C₆-alkylcarbonylamino, N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkanoyl, or phenyl, which isunsubstituted or substituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, cyano or nitro.

The term heterocyclyl may denote, for example, a 5- or 6-memberedheteroaryl radical having from 1 to 4, preferably from 1 to 3 same ordifferent heteroatoms selected from the group consisting of N, O and S,which is further unsubstituted or substituted by one or moresubstituents as defined above for heterocyclyl. The heteroaryl radicalis preferably substituted by 0 to 3, in particular 0, 1 or 2substituents from the group as defined above.

The term 5- or 6-membered heteroaryl, either alone or in terms such asheteroarylamino or heteroarylcarbonyl, may include, for example, athienyl, pyrryl, pyrazolyl, furyl, oxazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyrimidinyl or thiazinyl radical which is eachunsubstituted or substituted, for example, by halogen, cyano, nitro,C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄-alkoxy,C₂-C₄-alkanoyl, C₁-C₄-alkoxycarbonyl or unsubstituted or substitutedphenyl.

The term heterocyclyl may further denote a 3 to 6-memberedheterocycloalkyl radical having from 1 to 3 same or differentheteroatoms selected from the group consisting of B, N, O and S, whichis further unsubstituted or substituted by one or more substituents asdefined above for heterocyclyl. The heterocycloalkylene radical ispreferably substituted by 0 to 3, in particular 0, 1 or 2 substituentsfrom the group as defined above. Examples are tetrahydrofuranyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl or dioxoborolanylwhich is each unsubstituted or substituted by halogen, C₁-C₂-alkyl,C₁-C₂-haloalkyl or C₁-C₂-alkoxy.

Examples of heterocyclyloxy are 2-, 3- or 4-pyridyloxy orpyrimidin-4-yloxy, which is each unsubstituted or substituted byhalogen, C₁-C₂-alkyl, C₃-C₆-cycloalkyl, C₁-C₂-haloalkyl or C₁-C₂-alkoxy.

Examples of heterobicyclic ring radicals are benzoxazolyl,benzothiazolyl, tetrahydro-benzothiazolyl, indolyl, benzimidazolyl,benzopyrazolyl, 5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl,methylenedioxoyphenyl, benzooxaboronyl, chinolinyl,triazolopyrimidinonyl, for example1,2,3-triazolo[4,5-d]pyrimidin-7-one-5-yl, or phthalhydrazidyl, whichmay each be unsubstituted or substituted, for example, by halogen,cyano, C₁-C₄-alkyl, C₁-C₂-haloalkyl, hydroxy or C₁-C₂-alkoxy.

Concerning the variables contained in the compounds of formula (I), thefollowing meanings and preferences apply.

The variable n is preferably 1 if A is a phenyl radical. The variable nis preferably 0 if A is different from a phenyl radical, e.g. if A isC₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl; C₃-C₆-halocycloalkyl; a5- or 6-membered heterocycloalkyl radical, a heteroaromatic radical, ora hetero-bicyclic ring radical.

Preferred substituents of the phenyl radical A are halogen; C₁-C₄-alkyl;C₁-C₄-haloalkyl; amino; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-haloalkylthio; C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl;tri-C₁-C₂-alkylsilyl; C₁-C₄-alkoxycarbonyl; N-mono- orN,N-di-C₁-C₄-alkylaminocarbonyl; aminosulfonyl; N-mono- orN,N-di-C₁-C₄-alkylaminosulfonyl;N—C₁-C₂-alkyl-N—C₁-C₄-alkoxycarbonylamino; cyano; nitro; or 5- or6-membered heterocycloalkyl comprising 1 or 2 same or differentheteroatoms selected from O, S and N, which is unsubstituted orsubstituted by halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl or C₁-C₂-alkoxy.

More preferred substituents of the phenyl radical A are halogen;C₁-C₂-alkyl; C₁-C₄-haloalkyl; amino; C₁-C₄-alkoxy; C₁-C₄-haloalkoxy;C₁-C₄-alkylsulfonyl; C₁-C₄-haloalkylsulfonyl; trimethylsilyl;C₁-C₄-alkoxycarbonyl; N,N-di-C₁-C₂-alkylaminocarbonyl; aminosulfonyl;N,N-di-C₁-C₂-alkylaminosulfonyl;N—C₁-C₂-alkyl-N—C₁-C₄-alkoxycarbonylamino; cyano; nitro; or aheterocycloalkyl radical selected from the group consisting oftetrahydrofuranyl, pyrrolidinyl, morpholinyl and piperidinyl.

Especially preferred substituents of the phenyl radical A are halogen,C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy or cyano,and especially chlorine, fluorine or CF₃.

Specific preferred phenyl radicals A are 2-, 3- or 4-Cl-phenyl,4-CF₃-phenyl, 3,5-di-Cl-phenyl, 3,5-di-CF₃-phenyl, 2,4,6-tri-Cl-phenyl,3,4,5-tri-Cl-phenyl, 2-Cl-4-CF₃-phenyl, 2-CF₃-4-Cl-phenyl or2,6-di-Cl-4-CF₃-phenyl, in particular 4-Cl-phenyl.

A as C₁-C₆-alkyl is preferably C₁-C₄-alkyl. A as haloalkyl is preferablyC₁-C₂-haloalkyl, in particular CF₃.

A as 5- or 6-membered heterocycloalkyl is preferably a pyrrolidinyl,piperazinyl, morpholinyl or dioxaborolanyl, which is each unsubstitutedor substituted by methyl.

A as a heteroaromatic radical is preferably pyrryl, pyrazolyl,triazolyl, thienyl, thiazinyl, thiazolyl, pyridyl or pyrimidinyl, whichis each unsubstituted or substituted by halogen, cyano, C₁-C₂-alkyl,C₁-C₂-alkoxy, C₁-C₂-haloalkyl, acetyl, propionyl, phenyl ormorpholin-4-yl-methyl. Particularly preferred meanings of A asheteroaromatic radical are 2-, 3- or 4-pyridyl which is unsubstituted orsubstituted by halogen, cyano, C₁-C₂-alkoxy, acetyl or propionyl;pyrimidinyl which is unsubstituted or substituted by halogen or acetyl;1,2,4-triazol-5-yl which is unsubstituted or substituted by phenyl;thienyl which is unsubstituted or substituted by halogen, acetyl ormorpholin-4-yl-methyl; pyrazol-1-yl or -5-yl which is each unsubstitutedor substituted by methyl; or thiazin-4-yl.

A as a hetero-bicyclic ring radical is preferably indolyl,benzopyrazolyl or benzothiazol, which is each unsubstituted orsubstituted by methyl.

According to a preferred embodiment of the invention A is C₁-C₄-alkyl;C₁-C₂-haloalkyl; heterocycloalkyl selected from pyrrolidinyl,piperazinyl, morpholinyl and dioxaborolanyl, which is each unsubstitutedor substituted by methyl; a heteroaromatic radical selected from pyrryl,pyrazolyl, triazolyl, thienyl, thiazinyl, thiazolyl, pyridyl andpyrimidinyl, which is each unsubstituted or substituted by halogen,cyano, C₁-C₂-alkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkyl, acetyl, propionyl,phenyl or morpholin-4-yl-methyl; or a hetero-bicyclic ring radicalselected from indolyl, benzopyrazolyl and benzothiazol, which is eachunsubstituted or substituted by methyl.

The variable R² is preferably H.

T as alkyl radical is preferably C₁-C₄-alkyl, which is unsubstituted orsubstituted by halogen, cyclopropyl, cyclohexyl, trimethylsilyl, carboxyor C₁-C₂-alkoxycarbonyl. Particularly preferred meanings of T as alkylradical are C₁-C₄-alkyl; C₁-C₃-haloalkyl, in particular CF₃, —CH₂—CF₃ or—CH₂—CH₂—CF₃; trimethylsilyl-C₁-C₂-alkyl; C₁-C₂-alkoxycarbonylmethyl;carboxymethyl; or cyclohexylmethyl; especially methyl.

T as C₃-C₆-cycloalkyl, in preferably cyclopropyl or cyclohexyl.

T as bicarbocyclyl is, for example, a bicycloalkylene orbicycloalkylenone radical, for example1,7,7-trimethylbicyclo[2.2.1]heptyl or1,7,7-trimethylbicyclo[2.2.1]heptan-2-one-yl ((+)- or (−)-camphor).

T as phenyl radical is preferably phenyl which is unsubstituted orsubstituted by fluorine, chlorine, methyl, methoxy, CF₃ or nitro.

T as heteroaromatic radical is preferably pyridyl, thienyl orpyrimidinyl.

T as heterocycloalkyl is preferably piperidinyl, piperazinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl orthiomorpholin-4-yl-1,1-dioxide, which is each unsubstituted orsubstituted by methyl or benzyloxycarbonyl. Particularly preferredheterocyclyl radicals T are 1-methylpiperazin-4-yl,1-(benzyloxycarbonyl)-piperazin-4-yl, tetrahydro-2H-pyran-4-yl or,thiomorpholin-4-yl-1,1-dioxide.

R³ is preferably methyl, halophenyl, trifluoromethylpyridyl,tert.-butoxycarbonylmethyl or morpholin-4-yloxycarbonylmethyl.

T is preferably C₁-C₄-alkyl; C₁-C₃-haloalkyl;trimethylsilyl-C₁-C₂-alkyl; C₁-C₂-alkoxycarbonylmethyl; carboxymethyl;cyclohexylmethyl; C₃-C₆-cycloalkyl; 1,7,7-trimethylbicyclo[2.2.1]heptylor 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one-yl((+)- or (−)-camphor);phenyl which is unsubstituted or substituted by fluorine, chlorine,methyl, methoxy, CF₃ or nitro; pyridyl, thienyl or pyrimidinyl;heterocycloalkyl selected from piperidinyl, piperazinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl orthiomorpholin-4-yl-1,1-dioxide, which is each unsubstituted orsubstituted by methyl or benzyloxycarbonyl; or a group

wherein R³ is methyl, halophenyl, trifluoromethylpyridyl,tert.-butoxycarbonylmethyl or morpholin-4-yloxycarbonylmethyl.

R⁰ is preferably H.

Preferred substituents of the phenyl or phenylamino radical Y arehalogen; C₁-C₄-alkyl; C₁-C₄-haloalkyl; C₃-C₆-cycloalkyl; C₁-C₄-alkoxy;C₁-C₄-haloalkoxy; C₁-C₄-haloalkylthio; SF₅;N,N-di-C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl;N—C₁-C₄-alkylsulfonylamino; cyano; nitro; hydroxy; B(OH)₂ ormethylsulfonylamino.

More preferred substituents of the phenyl or phenylamino radical Y arehalogen; C₁-C₂-alkyl; C₁-C₃-haloalkyl; C₁-C₂-alkoxy; C₁-C₃-haloalkoxy;C₁-C₂-haloalkylthio; SF₅; cyano; nitro; hydroxy; or methylsulfonylamino.

Particularly preferred substituents of the phenyl or phenylamino radicalY halogen, methyl, C₁-C₃-haloalkyl, methoxy, C₁-C₃-haloalkoxy, SCF₃,SF₅, cyano, nitro or hydroxy and especially halogen or CF₃.

A specific preferred phenyl radical Y is 3,4,5-trichlorophenyl,3,5-di-trifluoromethyl-4-chlorophenyl and 3,5-di-trifluoromethylphenyl.

A specific preferred phenylamino radical Y is phenyl amino which issubstituted by chlorine, bromine, methyl trifluoromethyl, methoxy, cyanoor nitro.

A heteroaryl radical Y is, for example, pyrryl, pyrazolyl, oxazolyl,thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl or pyrimidinyl,which is each unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-alkoxycarbonyl, orphenyl or phenylsulfonyl which is in turn each unsubstituted orsubstituted by halogen, cyano, nitro methyl or methoxy.

A heteroaryl radical Y is preferably 2-, 3- or 4-pyridyl which isunsubstituted or substituted by halogen, C₁-C₄-alkyl or C₁-C₂-alkoxy;2-thienyl, which is unsubstituted or substituted by C₁-C₂-alkyl orC₁-C₂-alkoxycarbonyl; 2-thiazolyl, which is unsubstituted or substitutedby halogen, cyano, nitro, C₁-C₂-alkyl, C₁-C₂-haloalkyl,C₁-C₂-alkoxycarbonyl, or phenyl or phenylsulfonyl which is in turn eachunsubstituted opr substituted by halogen, cyano, nitro or methyl;5-isothiazoyl which is unsubstituted or substituted by halogen ormethyl; 2-oxazolyl, which is unsubstituted or substituted by C₁-C₂-alkylor C₁-C₂-haloalkyl; or 1,3,4-thiadiazol-5-yl, which is unsubstituted orsubstituted by C₁-C₂-alkyl or C₁-C₂-haloalkyl.

A heteroarylamino radical Y is preferably 2-, 3- or 4-pyridylamino,which is unsubstituted or substituted by halogen, C₁-C₄-alkyl orC₁-C₂-alkoxy.

A benzoyl or heteroarylcarbonyl radical Y is preferably benzoyl, whichis unsubstituted or substituted by halogen; or 2-, 3- or4-pyridylcarbonyl which is unsubstituted or substituted by halogen orC₁-C₄-alkyl.

A preferred bicarbocyclic radical Y is preferably a radical

a radical

or indanyl.

A preferred heterobicyclic ring radical Y is benzothiazolyl, indolyl,chinolinyl, methylenedioxophenyl, benzooxaboronyl, triazolopyrimidinonylor phthalhydrazidyl, which is each be unsubstituted or substituted byhalogen, C₁-C₄-alkyl, C₁-C₂-haloalkyl, C₁-C₄-alkoxy or hydroxy.

The variable R⁴ is preferably propynyl, 2,2,2-trifluoroethyl orcyanomethyl.

A preferred radical Y is thus (i) phenyl or phenylamino which issubstituted by halogen, C₁-C₂-alkyl, C₁-C₃-haloalkyl, C₁-C₂-alkoxy,C₁-C₃-haloalkoxy, C₁-C₂-haloalkylthio, SF₅, cyano, nitro, hydroxy ormethylsulfonylamino; (iia) heteroaryl selected from 2-, 3- or 4-pyridylwhich is unsubstituted or substituted by halogen, C₁-C₄-alkyl orC₁-C₂-alkoxy, 2-thienyl, which is unsubstituted or substituted byC₁-C₂-alkyl or C₁-C₂-alkoxycarbonyl, 2-thiazolyl, which is unsubstitutedor substituted by halogen, cyano, nitro, C₁-C₂-alkyl, C₁-C₂-haloalkyl,C₁-C₂-alkoxycarbonyl, or phenyl or phenylsulfonyl which is in turn eachunsubstituted or substituted by halogen, cyano, nitro or methyl,5-isothiazoyl which is unsubstituted or substituted by halogen ormethyl, 2-oxazolyl, which is unsubstituted or substituted by C₁-C₂-alkylor C₁-C₂-haloalkyl, or 1,3,4-thiadiazol-5-yl, which is unsubstituted orsubstituted by C₁-C₂-alkyl or C₁-C₂-haloalkyl; (iib) heteroarylaminoselected from 2-, 3- or 4-pyridylamino, which is unsubstituted orsubstituted by halogen, C₁-C₄-alkyl or C₁-C₂-alkoxy; (iii) benzoyl,which is unsubstituted or substituted by halogen, or 2-, 3- or4-pyridylcarbonyl which is unsubstituted or substituted by halogen orC₁-C₄-alkyl; (iv) a bicarbocyclic radical selected from a radical

a radical

and indanyl; (v) a heterobicyclic ring radical selected frombenzothiazolyl, indolyl, chinolinyl, methylenedioxophenyl,benzooxaboronyl, triazolopyrimidinonyl and phthalhydrazidyl, which iseach be unsubstituted or substituted by halogen, C₁-C₄-alkyl,C₁-C₂-haloalkyl, C₁-C₄-alkoxy or hydroxy; or (vi) a radicalH₂C—C(O)—NH—R⁴, wherein R⁴ is propynyl, 2,2,2-trifluoroethyl orcyanomethyl.

If R⁰ and Y together with the N-atom to which they are attached, form apiperidinyl or piperazinyl radical, said piperidinyl or piperazinylradical is preferably substituted by methyl; methoxy; halogen-, amino-,methoxy- or trifluoromethyl-substituted phenyl or benzoylamino; orhalogen-, trifluoromethyl- and/or cyclopropyl-substituted pyridyl orpyrimidinyl.

One embodiment of the present invention concerns a compound of formula

wherein n has the above-given meaning including the preferences, Y′ isphenyl which is substituted as mentioned above including thepreferences; and A′ is C₁-C₆-alkyl; C₁-C₆-haloalkyl; C₃-C₆-cycloalkyl;C₃-C₆-halocycloalkyl; 5- or 6-membered heterocycloalkyl having from 1 to3 same or different heteroatoms selected from the group consisting of B,N, O and S, which is further unsubstituted or substituted by halogen,C₁-C₄-alkyl or C₁-C₄-alkoxy; a heteroaromatic radical, which is furtherunsubstituted or substituted by halogen, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkanoyl, 5- or6-membered heterocycloalkyl-C₁-C₂-alkyl or unsubstituted or halogen-,C₁-C₄-alkyl- or C₁-C₄-alkoxy-substituted phenyl; or is a hetero-bicyclicring radical comprising a total of 8 to 10 ring members, from which 1 to5, preferably 1 or 2, members are same or different heteroatoms selectedfrom the group consisting of B, N, O and S, and from which 0 to 2members are a group C(O)—, which bicyclic ring radical is furtherunsubstituted or substituted by halogen, cyano, hydroxyl, C₁-C₄-alkoxy,C₁-C₄-alkyl or C₁-C₄-haloalkyl.

A compound of formula (Ia), wherein Y′ is phenyl which is substituted by2 or 3 same or different radicals selected from halogen or CF₃; and A′is C₁-C₄-alkyl; CF₃; pyrrolidinyl, piperazinyl, morpholinyl ordioxaborolanyl, which is each unsubstituted or substituted by methyl;pyrryl, pyrazolyl, triazolyl, thienyl, thiazinyl, thiazolyl, pyridyl orpyrimidinyl, which is each unsubstituted or substituted by halogen,cyano, C₁-C₂-alkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkyl, acetyl, propionyl,phenyl or morpholin-4-yl-methyl; or indolyl, benzopyrazolyl orbenzothiazolyl, which is each unsubstituted or substituted by methyl ormethoxy; and n is 0 or 1, in particular 1; is especially preferred.

A further preferred embodiment of the present invention concerns acompound of formula

wherein A is phenyl which is unsubstituted or substituted as mentionedabove including the preferences, Y is phenyl which is substituted asmentioned above including the preferences, T is C₂-C₆-alkyl, which isunsubstituted or substituted by halogen, trimethylsilyl,C₃-C₆-cycloalkyl, carboxy or C₁-C₄-alkoxycarbonyl; C₃-C₆-cycloalkyl;C₆-C₁₂-bicarbocyclyl; phenyl which is unsubstituted or substituted byhalogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl or C₁-C₄-alkoxy; a5- or 6 membered heteroaromatic radical, which is further unsubstitutedor substituted by halogen, C₁-C₄-alkyl or C₁-C₄-alkoxy; amino; N-mono-or N,N-di-C₁-C₄-alkylamino; 5- or 6-membered heterocycloalkyl havingfrom 1 to 3 same or different heteroatoms selected from the groupconsisting of N, O, S and S(O₂), which is further unsubstituted orsubstituted by C₁-C₄-alkyl; or a group

and R³ is C₁-C₄-alkyl, unsubstituted or halogen-, C₁-C₄-alkyl- orC₁-C₄-haloalkyl-substituted phenyl, unsubstituted or halogen-,C₁-C₄-alkyl- or C₁-C₄-haloalkyl-substituted pyridyl,C₁-C₄-alkoxycarbonylmethyl or morpholin-4-yl-carbonylmethyl.

A preferred embodiment relates to a compound of formula (Ib), wherein Ais phenyl which is unsubstituted or preferably mono-substituted bychlorine, fluorine or CF₃, Y is phenyl which is substituted by 2 or 3same or different radicals selected from halogen or CF₃, and T isC₂-C₄-alkyl, which is unsubstituted or substituted by halogen,cyclopropyl, cyclohexyl, trimethylsilyl, carboxy or C₁-C₂-alkoxycarbony;cyclopropyl or cyclohexyl; the radical of (+)- or (−)-camphor; phenylwhich is unsubstituted or substituted by fluorine, chlorine, methyl,methoxy, CF₃ or nitro; or pyridyl, thienyl or pyrimidinyl; piperidinyl,piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl orthiomorpholin-4-yl-1,1-dioxide, which is each unsubstituted orsubstituted by methyl or benzyloxycarbonyl.

A further preferred embodiment of the present invention concerns acompound of formula

wherein A is phenyl which is unsubstituted or substituted as mentionedabove including the preferences, R⁰ is H or hydroxyl; and Y″ is

(i) 5- or 6 membered heteroaryl or heteroarylamino, which is eachfurther unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl,C₁-C₄-alkanoyl or phenyl or phenylsulfonyl which is each unsubstitutedor substituted by halogen, cyano, nitro methyl or methoxy; or is

(ii) benzoyl or 5- or 6 membered heteroarylcarbonyl, which is eachfurther unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl,C₁-C₄-alkanoyl or phenyl; or is

(iii) a C₆-C₁₂-bicarbocyclic radical; or is a

(iv) a hetero-bicyclic ring radical comprising a total of 8 to 10 ringmembers, from which 1 to 5, preferably 1 or 2, are same or differentheteroatoms selected from the group consisting of B, N, O and S, andfrom which 0 to 2 are a group C(O)—, which bicyclic ring radical isfurther unsubstituted or substituted by halogen, cyano, hydroxyl,C₁-C₄-alkyl, C₁-C₄-alkoxy or C₁-C₄-haloalkyl; or is

(v) a radical H₂C—C(O)—NH—R⁴, wherein R⁴ is C₁-C₄-haloalkyl,C₂-C₃-alkynyl or cyano-C₁-C₄-alkyl; or R⁰ and Y together with the N-atomto which they are attached, form a piperidinyl or piperazinyl radicalwhich is substituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, unsubstituted orhalogen-, C₁-C₄-alkyl-, halo-C₁-C₄-alkyl-, amino- and/orC₁-C₄-alkoxy-substituted phenyl or benzoylamino, or unsubstituted orC₁-C₄-alkyl-, C₁-C₄-haloalkyl-, C₃-C₆-cycloalkyl- or halogen-substitutedpyridyl or pyrimidinyl.

Concerning a preferred embodiment of the compounds of formula (Ic), A isphenyl which is unsubstituted or preferably mono-substituted bychlorine, fluorine or CF₃; R⁰ is H, and Y″ is

(i) 2-, 3- or 4-pyridyl which is unsubstituted or substituted byhalogen, C₁-C₄-alkyl or C₁-C₂-alkoxy; 2-thienyl, which is unsubstitutedor substituted by C₁-C₂-alkyl, C₁-C₂-alkoxycarbonyl; 2-thiazolyl, whichis unsubstituted or substituted by halogen, cyano, nitro, C₁-C₂-alkyl,C₁-C₂-haloalkyl, C₁-C₂-alkoxycarbonyl, or phenyl or phenylsulfonyl whichis in turn each unsubstituted opr substituted by halogen, cyano, nitroor methyl; 5-isothiazoyl which is unsubstituted or substituted byhalogen or methyl; 2-oxazolyl, which is unsubstituted or substituted byC₁-C₂-alkyl or C₁-C₂-haloalkyl; or 1,3,4-thiadiazol-5-yl, which isunsubstituted or substituted by C₁-C₂-alkyl or C₁-C₂-haloalkyl; 2-, 3-or 4-pyridylamino, which is unsubstituted or substituted by halogen,C₁-C₄-alkyl or C₁-C₄-alkoxy; or

(ii) benzoyl, which is unsubstituted or substituted by halogen or 2-, 3-or 4-pyridylcarbonyl which is unsubstituted or substituted by halogen orC₁-C₄-alkyl; or

(iii) a radical

a radical

or indanyl; or

(iv) benzothiazolyl, indolyl, chinolinyl, methylenedioxophenyl,benzooxaboronyl, triazolopyrimidinonyl or phthalhydrazidyl, which iseach be unsubstituted or substituted by halogen, C₁-C₄-alkyl,C₁-C₂-haloalkyl or hydroxy; or

(v) a radical H₂C—C(O)—NH—CH₂—C≡CH, H₂C—C(O)—NH—CH₂—CN or H₂C—C(O)—NH—CH₂—CF₃; or R⁰ and Y together with the N-atom to which they areattached, form a piperidinyl or piperazinyl radical, which issubstituted by methyl; methoxy; halogen-, amino-, methoxy- ortrifluoromethyl-substituted phenyl or benzoylamino; or halogen-,trifluoromethyl- and/or cyclopropyl-substituted pyridyl or pyrimidinyl.

A salt of a compound or formula (I) may be produced in known manner.Acid addition salts, for example, are obtainable by treatment with asuitable acid or a suitable ion exchange reagent, and salts with basesare obtainable by treatment with a suitable base or a suitable ionexchange reagent.

Salts of compounds of formula (I) can be converted into the freecompounds by the usual means, acid addition salts e.g. by treating witha suitable basic composition or with a suitable ion exchange reagent,and salts with bases e.g. by treating with a suitable acid or a suitableion exchange reagent.

Salts of compounds of formula (I) can be converted into other salts ofcompounds of the formula (I) in a known manner; acid addition salts canbe converted for example into other acid addition salts, e.g. bytreating a salt of an inorganic acid, such as a hydrochloride, with asuitable metal salt, such as a sodium, barium, or silver salt, of anacid, e.g. with silver acetate, in a suitable solvent, in which aresulting inorganic salt, e.g. silver chloride, is insoluble and thusprecipitates out from the reaction mixture.

Depending on the method and/or reaction conditions, the compounds offormula (I) with salt-forming characteristics can be obtained in freeform or in the form of salts. Compounds of formula (I) can also beobtained in the form of their hydrates and/or also can include othersolvents, used for example where necessary for the crystallisation ofcompounds present in solid form.

As mentioned before, the compounds of formula (I) may be optionallypresent as optical and/or geometric isomers or as a mixture thereof. Theinvention relates both to the pure isomers and to all possible isomericmixtures, and is hereinbefore and hereinafter understood as doing so,even if stereochemical details are not specifically mentioned in everycase.

Diastereoisomeric mixtures of compounds of formula (I), which areobtainable by the process or in another way, may be separated in knownmanner, on the basis of the physical-chemical differences in theircomponents, into the pure diastereoisomers, for example by fractionalcrystallisation, distillation and/or chromatography.

Splitting of mixtures of enantiomers, that are obtainable accordingly,into the pure isomers, may be achieved by known methods, for example byrecrystallisation from an optically active solvent, by chromatography onchiral adsorbents, e.g. high-pressure liquid chromatography (HPLC) onacetyl cellulose, with the assistance of appropriate micro-organisms, bycleavage with specific immobilised enzymes, through the formation ofinclusion compounds, e.g. using chiral crown ethers, whereby only oneenantiomer is complexed.

The compounds of the formula (I), wherein n is 0, may be prepared, forexample, by reaction of a compound of formula

wherein R⁰, R², T and Y are each as defined above and LG is a leavinggroup, for example halogen such as bromine, with a compound of formula

in the presence of a palladium catalyst, wherein A is defined above. Thedetails of this palladium-catalyzed carbon-carbon bond forming reaction,called Suzuki reaction, are known from textbooks of organic chemistry.

The compounds of formula (II) are known or may be prepared according toknown processes, for example by reacting a compound of formula

with a compound of formula

wherein LG′ is a leaving group, for example halogen, C₁-C₂-alkoxy orhydroxyl, and the further variables each have the above mentionedmeaning. The amide formation from an carboxylic acid or an derivativethereof with an amine is known from textbooks of organic chemistry. Thecompounds of formula (IV) are known or may be prepared according toknown processes, for example by reacting the corresponding amine withmethane sulfonyl chloride in known manner. The compounds of formula(III) and (V) are known compounds which are commercially available.

Certain compounds of the formula (I), wherein n is 0, may also beprepared, for example, by reaction of a compound of formula

wherein R⁰, R², T and Y are each as defined above and LG is a leavinggroup, for example halogen such as bromine or chlorine, with a compoundof formula

wherein A* is a heterocyclic radical A and the H-atom is attached to aheteroatom, for example N or O, by way of an electrophilic substitutionat the phenyl ring. The compounds of formula (Ha) may be obtained inanalogy to the compounds of formula of formula (II) above.

The compounds of the formula (I), wherein n is 1, may be prepared, forexample, by reaction of a compound of formula

with a compound of formula

wherein the variables are as defined above, followed by the reduction ofthe nitro group and further reacting the resulting amine with methanesulfonyl chloride. The details of these reactions are known fromtextbooks of organic chemistry. The compounds of formula (VI) may beprepared in analogy to the compounds of formula (II). The compounds offormula (VII) are known per se and are commercially available.

The compounds of the formula (I), wherein n is 1 may also be prepared byreaction of a compound of formula

with a compound of formula

wherein the variables each have the above given meaning, followed by thereduction of the nitro group and further reacting the resulting aminewith methane sulfonyl chloride. In the alternative, the nitro group ofthe compound of formula (VIII) may first of all be reduced and theresulting amino group be reacted with methane sulfonyl chloride, beforethe reaction with the compound of formula (V) is performed.

The compounds of formula (VIII) may be prepared in a manner known perse, for example by reaction of a compound of formula

with a compound of formula

The Examples further illustrate the different synthesis methods.

The compounds of formula (I) according to the invention are notable fortheir broad activity spectrum and are valuable active ingredients foruse in pest control, including in particular the control ofendoparasites, especially helminths, in and on warm-blooded animals,especially productive livestock and pets, whilst being well-tolerated bywarm-blooded animals and fish.

Productive livestock includes mammals such as, for example, cattle,horses, sheep, pigs, goats, donkeys, rabbits, deer, as well as birds,for example chickens, geese, turkeys, ducks and exotic birds.

Pets include, for example, dogs, cats and hamsters, in particular dogsand cats. The compounds of formula (I) of the present invention areeffective against helminths, in which the endoparasitic nematodes andtrematodes may be the cause of serious diseases of mammals and poultry.Typical nematodes of this indication are: Filariidae, Setariidae,Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia,Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus,Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia,Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Thetrematodes include, in particular, the family of Fasciolideae,especially Fasciola hepatica (liver fluke).

It could also be shown surprisingly and unexpectedly that thecompositions of the present invention have exceptionally high efficacyagainst nematodes that are resistant to many active substances. This canbe demonstrated, for example in vitro by the LDA test.

Certain pests of the species Nematodirus, Cooperia and Oesophagostonuminfest the intestinal tract of the host animal, while others of thespecies Haemonchus and Ostertagia are parasitic in the stomach and thoseof the species Dictyocaulus are parasitic in the lung tissue. Parasitesof the families and may be found in the internal cell tissue and in theorgans, e.g. the heart, the blood vessels, the lymph vessels and thesubcutaneous tissue. A particularly notable parasite is the heartworm ofthe dog, Dirofilaria immitis. The compounds of formula (I) according tothe present invention are highly effective against these parasites.

The pests which may be controlled by the compounds of formula (I) of thepresent invention also include those from the class of Cestoda(tapeworms), e.g. the families Mesocestoidae, especially of the genusMesocestoides, in particular M. lineatus; Dipylidiidae, especiallyDipylidium caninum, Joyeuxiella spp., in particular Joyeuxiellapasquali, and Diplopylidium spp., and Taeniidae, especially Taeniapisiformis, Taenia cervi, Taenia ovis, Taeneia hydatigena, Taeniamulticeps, Taenia taeniaeformis, Taenia serialis, and Echinococcus spp.,most preferably Taenia hydatigena, Taenia ovis, Taenia multiceps, Taeniaserialis; Echinococcus granulosus and Echinococcus multilocularis.

Furthermore, the compounds of formula (I) are suitable for the controlof human pathogenic parasites. Of these, typical representatives thatappear in the digestive tract are those of the genus Ancylostoma,Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris andEnterobius. The compounds of the present invention are also effectiveagainst parasites of the genus Wuchereria, Brugia, Onchocerca and Loafrom the family of Dracunculus and parasites of the genus Strongyloidesand Trichinella, which infect the gastrointestinal tract in particular.

The good endoparasiticidal activity of the compounds of formula (I)corresponds to a mortality rate of at least 50-60%, in particular atleast 80% and especially at least 90% of the endoparasites mentioned.

Administration of the compounds of formula (I) according to theinvention may be effected therapeutically or preferablyprophylactically.

Application of the compounds of formula (I) according to the inventionto the animals to be treated may take place, for example, topically,perorally, parenterally or subcutaneously. A preferred embodiment of theinvention relates to compounds of formula (I) for parenteral use or, inparticular, for peroral use.

Preferred application forms for usage on warm-blooded animals in thecontrol of nematodes/helminths comprise solutions; emulsions includingclassical emulsions, microemulsions and self-emulsifying compositions,that are waterless organic, preferably oily, compositions which formemulsions—together with body fluids—upon addition to an animal body;suspensions (drenches); pour-on formulations; food additives; powders;tablets including effervescent tablets; boli; capsules includingmicro-capsules; and chewable treats; whereby the physiologicalcompatibility of the formulation excipients must be taken intoconsideration. Particularly preferred application forms are tablets,capsules, food additives or chewable treats.

The compounds of formula (I) of the present invention are employed inunmodified form or preferably together with adjuvants conventionallyused in the art of formulation and may therefore be processed in a knownmanner to give, for example, emulsifiable concentrates, directlydilutable solutions, dilute emulsions, soluble powders, powder mixtures,granules or microencapsulations in polymeric substances. As with thecompositions, the methods of application are selected in accordance withthe intended objectives and the prevailing circumstances.

The formulation, i.e. the agents, preparations or compositionscontaining the one or more active ingredients and optionally a solid orliquid adjuvant, are produced in a manner known per se, for example byintimately mixing and/or grinding the active ingredients with theadjuvants, for example with solvents, solid carriers and/orsurface-active compounds (surfactants).

The solvents in question may be: alcohols, such as ethanol, propanol orbutanol, and glycols and their ethers and esters, such as propyleneglycol, dipropylene glycol ether, ethylene glycol, ethylene glycolmonomethyl or -ethyl ether, ketones, such as cyclohexanone, isophoroneor diacetanol alcohol, strong polar solvents, such asN-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, orwater, vegetable oils, such as rape, castor, coconut, or soybean oil,and also, if appropriate, silicone oils.

Suitable surfactants are, for example, non-ionic surfactants, such as,for example, nonylphenolpolyethoxyethanols; castor oil polyglycolethers, for example macrogol glycerolhydroxystearate 40; polyethyleneglycols; polypropylene/polyethylene oxide adducts; or fatty acid estersof polyoxyethylene sorbitan, e.g. polyoxyethylene sorbitan monooleate.

Solid carriers, for example for tablets and boli, may be chemicallymodified polymeric natural substances that are soluble in water or inalcohol, such as starch, cellulose or protein derivatives (e.g. methylcellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose,proteins such as zein, gelatin and the like), as well as syntheticpolymers, such as polyvinyl alcohol, polyvinyl pyrrolidone etc. Thetablets also contain fillers (e.g. starch, microcrystalline cellulose,sugar, lactose etc.), glidants and disintegrants.

If the anthelminthics are present in the form of feed concentrates, thenthe carriers used are e.g. performance feeds, feed grain or proteinconcentrates. Such feed concentrates or compositions may contain, apartfrom the active ingredients, also additives, vitamins, antibiotics,chemotherapeutics or other pesticides, primarily bacteriostats,fungistats, coccidiostats, or even hormone preparations, substanceshaving anabolic action or substances which promote growth, which affectthe quality of meat of animals for slaughter or which are beneficial tothe organism in another way.

Suitable compositions of the compounds of formula (I) may also containfurther additives, such as stabilisers, antioxidants, for exampletocopherols like α-tocopherol, anti-foaming agents, viscosityregulators, binding agents, colors or tackifiers, as well as otheractive ingredients, in order to achieve special effects. Preferably, thecomposition comprises from 0.001 to 1% w/v of one or more antioxidants.If desired, the formulations of the present invention may comprise acolor, for example in an amount of from 0.001 to 1% w/v.

As a rule, an anthelminthic composition according to the inventioncontains 0.1 to 99% by weight, especially 0.1 to 95% by weight of acompound of formula (I), 99.9 to 1% by weight, especially 99.8 to 5% byweight of a solid or liquid admixture, including 0 to 25% by weight,especially 0.1 to 25% by weight of a surfactant.

In each of the processes according to the invention for pest control orin each of the pest control compositions according to the invention, thecompounds of formula (I) can be used in all of their stericconfigurations or in mixtures thereof.

The invention also includes a method of prophylactically protectingwarm-blooded animals, especially productive livestock and pets, inparticular dogs or cats, against parasitic helminths, which ischaracterised in that a compound of formula (I) or the active ingredientformulation prepared therefrom is administered to the warm-bloodedanimal as an additive to the feed, or to the drinks or also in solid orliquid form, orally or by injection or parenterally. The invention alsoincludes the compounds of formula (I) according to the invention forusage in one of the said processes.

The compounds of formula (I) according to the invention may be usedalone or in combination with other biocides. They may be combined withpesticides having the same sphere of activity e.g. to increase activity,or with substances having another sphere of activity e.g. to broaden therange of activity. It can also be sensible to add so-called repellents.

The following Examples illustrate the invention further.

Analysis of the purified samples is in each case done using a WatersAutopurification (HPLC/MS) system with a reversed phase column usingmethod B described below. The samples are characterized by m/z andretention time. The above-given retention times relate in each case tothe use of a solvent system comprising two different solvents, solventA: H₂O+0.01% HCOOH, and solvent B: CH₃CN+0.01% HCOOH).

-   -   Method B: column Waters XTerra MS C18 μm, 50×4.6 mm (Waters),        flow rate of 3.00 mL/min with a time-dependent gradient as given        in the Table:

Time [min] A [%] B [%] 0 90 10 0.5 90 10 2.5 5 95 2.8 5 95 2.9 90 10 3.090 10

Example 1A Synthesis of2-(methylsulfonamido)-5-morpholino-N-(3,4,5-trichlorophenyl)benzamide(Ex. 1.2 in Table 1) Step A: 5-chloro-2-nitro-N-(3,4,5-trichlorophenyl)benzamide

5-chloro-2-nitrobenzoic acid (10 g) was treated with thionyl chloride(7.2 mL) at reflux for 4 h. Excess SOCl₂ was removed under vacuum.CH₂Cl₂ (100 mL) was added to the acyl chloride. At 0° C.,3,4,5-trichloroaniline (9.7 g) and NEt₃ (13.8 mL) in 100 mL CH₂Cl₂ wereadded slowly. The reaction mixture was allowed to warm up and it wasstirred at rt (room temperature) overnight. The reaction mixture wasdiluted with 200 mL diethyl ether. 10 mL HCl 2 N and 200 mL H₂O wereadded, and the mixture was stirred until a yellow precipitate is formed.The precipitate was filtered off and dried under high vacuum beforeanalysis (yield: 66%). LCMS (method B): 380.59 (M+H)⁺ at 1.97 min.

Step B: 5-morpholino-2-nitro-N-(3,4,5-trichlorophenyl)benzamide

To a solution of 300 mg of5-chloro-2-nitro-N-(3,4,5-trichlorophenyl)benzamide in 1.5 nil, DMF, wasadded morpholine (206 μL). The reaction mixture was heated at 110° C.for 1.5 h. After work-up and extraction with AcOEt, the mixture wasevaporated to dryness. The title compound was pure enough to be engagedin step B. (yield: 71%). LCMS (method B): 427.7 (M−H)⁻ at 1.81 min.

Step C: 2-amino-5-morpholino-N-(3,4,5-trichlorophenyl)benzamide

Under N₂, 5-morpholino-2-nitro-N-(3,4,5-trichlorophenyl)benzamide (230mg) in 4 mL EtOH/H₂O (3/1) was treated with Fe (208 mg) and HCl 25% (4μL) and the reaction mixture was stirred at rt for 4 h. When thereduction was completed, the reaction mixture was filtered on a plug ofcelite and washed with ethyl acetate. The filtrate was evaporated undervacuum. Ethyl acetate was added, and the organic layer was washed withbrine, dried over MgSO₄, and evaporated to dryness (yield: 95%). LCMS(method B): 399.68 (M+H)⁺ at 1.61 min.

Step D:2-(methylsulfonamido)-5-morpholino-N-(3,4,5-trichlorophenyl)benzamide

A N₂ degassed solution of2-amino-5-morpholino-N-(3,4,5-trichlorophenyl)benzamide (193 mg) in 3 mLCH₂Cl₂, pyridine (0.194 mL) was added. The mixture was cooled to 0° C.before the drop wise addition of methane sulfonyl chloride (0.037 mL).The reaction mixture was stirred overnight at rt, then diluted with 50mL ethyl acetate. The organic layer was washed with a saturated solutionof Na₂CO₃, with brine, then dried over MgSO₄ and evaporated to dryness(yield: 43%). LCMS (method B): 477.7 (M+H)⁺ at 1.78 min.

Example 1B N-(3,5-bis (trifluoromethyl)phenyl)-5-(2-fluoropyridin-3-yl)-2-(methylsulfonamido) benzamide (Ex.1.14 in Table 1) Step A: methyl 5-bromo-2-(methylsulfonamido) benzoate

A N₂ degassed solution of methyl 2-amino-5-bromobenzoate (2.8 g) in 10mL 1 pyridine was cooled to 0° C. before the drop wise addition ofmethane sulfonyl chloride (0.9 mL). The reaction mixture was stirredovernight at rt, then diluted with 50 mL ethyl acetate. The organiclayer was washed with a saturated solution of Na₂CO₃, with brine, thendried over MgSO₄ and evaporated to dryness (yield: 82%). LCMS (methodB): 305.6 (M−H)⁻ at 1.55 min.

Step B: 5-bromo-2-(methylsulfonamido)benzoic acid

Methyl 5-bromo-2-(methylsulfonamido) benzoate (3.15 g) was suspended inTHF (20 mL, 1/1). NaOH 4 N (6.9 mL) was added and the reaction mixturewas stirred 4 h at reflux. Upon completion, the reaction mixture wastreated with 2N HCl (1 mL) and extracted twice with ethyl acetate.Combined organic layers were washed with H₂O, brine, dried over Na₂SO₄,filtered and evaporated to dryness. The title product was pure enough byLCMS to be engaged into next step without further purification. (yield:66%) LCMS (method B): 291.64 (M−H)⁻ at 1.2 min.

Step C:N-(3,5-bis(trifluoromethyl)phenyl)-5-bromo-2-(methylsulfonamido)benzamide

5-bromo-2-(methylsulfonamido) benzoic acid (2.4 g) was treated withthionyl chloride (23 mL) at reflux for 4 h. Excess SOCl₂ was removedunder vacuum. CH₂Cl₂ (20 mL) was added to the acyl chloride. At 0° C.,3,5-bis(trifluoromethyl)aniline (1.4 mL) and NEt₃ (5.68 mL) in 10 mLCH₂Cl₂ were added slowly. The reaction mixture was allowed to warm upand it was stirred at rt overnight.

The reaction mixture was diluted with 30 mL CH₂Cl₂. 20 mL HCl 2 N and 20mL H₂O were added, and the mixture was stirred until a yellowprecipitate is formed. The precipitate was filtered off and dried underhigh vacuum before analysis (yield: 67%). LCMS (method B): 502.93 (M−H)⁻at 1.99 min.

Step D: N-(3,5-bis (trifluoromethyl)phenyl)-5-(2-fluoropyridin-3-yl)-2-(methylsulfonamido) benzamide

To a solution ofN-(3,5-bis(trifluoromethyl)phenyl)-5-bromo-2-(methylsulfonamido)benzamide (0.2 g) and2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (133mg) under N₂ in dioxane/H₂O (6 mL, 1/1) was added Na₂CO₃ (252 mg),Pd(dppf)Cl₂.CH₂Cl₂ (355 mg). The reaction mixture was stirred for 3 h at80° C. It was diluted with ethyl acetate, filtered through celite. Thefiltrate was washed with H₂O, brine, dried over Na₂SO₄, filtered andevaporated to dryness.

The crude mixture was purified by flash chromatography eluting with agradient of 100% heptane to 60% heptane/40% ethyl acetate to offer thetitle compound in 25% yield. LCMS (method C): 521.8 (M+H)⁺ at 1.90 min.

The substances named in the following Table 1 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of A and (R)_(r) is given in Table 1.

The following physical data are obtained according to theabove-described HPLC/MS characterization process (method B). R_(r)refers to “retention time”.

TABLE 1 Ex. m/z: R_(t) [min] Physical No. A (R¹)_(r) [M + H⁺] (Method B)state 1.2 Morpholin-4-yl 3,4,5-tri-Cl 477.7 1.78 Solid 1.34-Methylpiperazin-1-yl 3,4,5-tri-Cl 490.9 1.29 Solid 1.4 Thiazin-4-yl3,4,5-tri-Cl 493.7 1.97 Solid 1.5 Pyrrolidin-1-yl 3,4,5-tri-Cl 461.72.04 Foam 1.6 Pyrazol-1-yl 3,4,5-tri-Cl 458.8 1.89 Powder 1.7 Isopropyl3,5-di-CF₃ 468.8 2.07 Powder 1.8 CF₃ 3,5-di-CF₃ 494.5 1.99 Oil 1.9

3,5-di-CF₃ 552.9 2.22 Powder 1.10

3,5-di-CF₃ 550.7 1.99 Powder 1.11

3,5-di-CF₃ 534.8 1.78 Solid 1.12

3,5-di-CF₃ 506.7 1.79 Powder 1.13

3,5-di-CF₃ 607.9 1.27 Resin 1.14

3,5-di-CF₃ 521.8 1.90 Powder 1.15

3,5-di-CF₃ 542.8 1.85 Powder 1.16

3,5-di-CF₃ 521.7 1.94 Powder 1.17

3,5-di-CF₃ 571.7 2.06 Foam 1.18

3,5-di-CF₃ 537.7 2.00 Powder 1.19

3,5-di-CF₃ 571.6 2.10 Powder 1.20

3,5-di-CF₃ 551.7 2.06 Powder 1.21

3,5-di-CF₃ 533.7 2.02 Powder 1.22

3,5-di-CF₃ 538.7 1.93 Powder 1.23

3,5-di-CF₃ 534.7 1.85 Powder 1.24

3,5-di-CF₃ 504.8 1.71 Powder 1.25

3,5-di-CF₃ 537.8 1.90 Solid 1.26

3,5-di-CF₃ 537.8 1.89 Foam 1.27

3,5-di-CF₃ 548.0 2.08 Powder 1.28

3,5-di-CF₃ 529.0 1.89 Powder 1.29

3,5-di-CF₃ 537.9 1.94 Powder 1.30

3,5-di-CF₃ 542.9 2.28 Powder 1.31

3,5-di-CF₃ 572.9 2.11 Powder 1.32

3,5-di-CF₃ 571.8 2.05 Powder 1.33

3,5-di-CF₃ 537.7 1.99 Resin

Example 25-phenoxy-2-(phenylsulfonamido)-N-(3,4,5-trichlorophenyl)benzamide (Ex.2.2 in Table 2) Step A:2-nitro-5-phenoxy-N-(3,4,5-trichlorophenyl)benzamide

5-Chloro-2-nitro-N-(3,4,5-trichlorophenyl) benzamide (29.1 g), K₂CO₃(21.3 g) and phenol (8 g) in DMA were heated at 140° C. during 14 h. Thereaction mixture was poured in H₂O (100 mL), the precipitate wasfiltered off, dried under high vacuum to afford a brown solid (yield:80%). LCMS (method B): 436.6 (M−H)⁻ at 2.14 min.

Step B: 2-amino-5-phenoxy-N-(3,4,5-trichlorophenyl)benzamide

2-nitro-5-phenoxy-N-(3,4,5-trichlorophenyl)benzamide treated with ironin a similar manner as described for step C Example 1 (yield: 27%). LCMS(method B): 406.7 (M+H)⁺ at 2.28 min.

Step C:5-(4-Chlorophenoxy)-2-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)benzamide

To N₂ degassed solution of2-amino-5-phenoxy-N-(3,4,5-trichlorophenyl)benzamide (0.26 mg) in 2 mLof CH₂Cl₂, pyridine (0.25 mL) was added. The mixture was cooled to 0° C.before the drop wise addition of benzene sulfonyl chloride (0.124 mg).The reaction mixture was stirred overnight at rt, then diluted withadditional 5 mL CH₂Cl₂. The organic layer was washed with a saturatedsolution of Na₂CO₃, with brine, then dried over MgSO₄ and evaporated todryness (yield: 81%). LCMS (method B): 546.7 (M+H)⁺ at 2.39 min.

The substances named in the following Table 2 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of (R¹)_(r), (R)_(m), and X are given in Table 2The following physical data are obtained according to theabove-described HPLC/MS characterization process (Method B).

TABLE 2 Ex. m/z: R_(t) Physical No. (R)_(m) T R² [M + H⁺] [min] state2.1 4-Cl 4-CH₃-phenyl 594.6 2.22 Powder 2.2 H phenyl H 546.7 2.39 Powder2.3 4-Cl 2-NO₂-4-CF₃-phenyl H 693.6 1.88 Gum 2.4 4-Cl 3-Cl-4-F-phenyl H632.5 2.57 Solid 2.5 4-Cl 2-CF₃-4-F-phenyl H 666.5 2.59 Solid 2.6 4-Cl4-CF₃-phenyl H 648.5 2.58 Solid 2.7 4-Cl 3,4-dimethoxyphenyl H 640.62.40 Solid 2.8 4-Cl 4-nitrophenyl H 625.5 2.46 Solid 2.9 4-Cl4-chlorophenyl H 614.7 2.59 Solid 2.10 4-Cl 3,5-di-Cl-phenyl H 648.52.78 Solid 2.11 4-Cl 4-methoxyphenyl H 610.6 2.46 Solid 2.12 4-Cl2-Chloro-phenyl H 614.5 2.57 Solid 2.13 4-Cl 3-Chlorophenyl H 614.7 2.60Solid 2.14 4-Cl 3-Pyridyl H 581.6 2.31 Solid 2.15 4-Cl 3-methoxyphenyl H610.6 2.49 Solid 2.16 4-Cl 3,4-dichlorophenyl H 648.5 2.71 Solid 2.174-Cl 2,6-dichlorophenyl H 648.6 2.66 Solid 2.18 4-Cl 2-methoxyphenyl H610.6 2.43 Solid 2.19 4-Cl 2,4-dichlorophenyl H 648.6 2.74 Solid 2.204-Cl 2-NO₂-4-OCH₃-phenyl H 655.5 2.42 Powder 2.21 4-Cl2,4-dimethoxyphenyl H 640.6 2.41 Solid 2.22 4-Cl ethyl H 532.5 2.37Solid 2.23 4-Cl —CH₂CF₃ H 586.4 2.39 Powder 2.24 4-Cl —CH₂CH₂CF₃ H 598.52.47 Solid 2.25 4-Cl n-propyl H 546.6 2.44 Solid 2.26 4-Cl n-butyl H560.7 2.52 Solid 2.27 4-Cl Iso-butyl H 560.7 2.51 Powder 2.28 4-Cl—CH₂CH₂Si(CH₃)₃ H 604.7 2.68 Powder 2.29 4-Cl Cyclopropyl H 544.6 2.36Powder 2.30 4-Cl Cyclohexyl H 586.6 2.65 Powder 2.31 4-Cl1-(benzyloxycarbonyl)- H 721.8 2.54 Powder piperazin-4-yl 2.32 4-ClIsopropyl H 546.6 2.23 Solid 2.33 4-Cl Cyclohexylmethyl H 600.6 2.74Solid 2.34 4-Cl (1R)-(−)-Campher H 654.7 2.57 Solid 2.35 4-Cl—CH₂C(O)OC₂H₅ H 590.6 2.36 Solid 2.36 4-Cl —CH₂C(O)OCH₃ H 576.6 2.29Foam 2.37 4-Cl —CH₂C(O)OH H 562.5 2.16 Solid 2.38 4-Cl (1S)-(+)-CampherH 654.8 2.55 Solid 2.39 4-Cl Tetrahydro-2H-pyran-4-yl H 588.6 2.33 Solid2.40 4-Cl —N(CH₃)₂ H 547.6 2.40 Powder 2.41 4-Cl 1-Methylpiperazin-4-ylH 602.8 1.72 Powder 2.42 4-Cl

H 637.6 2.24 Powder 2.43 4-Cl —CH₂—Cl —SO₂CH₂Cl 664.4 2.44 Solid 2.444-Cl

H 644.6 1.52 Powder 2.45 4-Cl

H 775.6 2.63 Powder 2.46 4-Cl

H 757.8 1.59 Powder 2.47 4-Cl

H 744.7 2.41 Powder 2.48 4-Cl

H 740.6 2.68 Powder

Example 32-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)-5-((2-(trifluoromethyl)pyridin-3-yl)oxy)benzamide(Ex 3.2 in Table 3) Step A: methyl 2-nitro-5-((2-(trifluoromethyl)pyridin-3-yl)oxy)benzoate

Methyl 5-chloro-2-nitrobenzoate was treated in a similar manner as stepA of synthesis of example 3 (yield: 28%). LCMS (method B): 342.86 (M+H)⁺at 1.63 min.

Step B: 2-nitro-5-((2-(trifluoromethyl) pyridin-3-yl)oxy)benzoic acid

Methyl 2-nitro-5-((2-(trifluoromethyl) pyridin-3-yl)oxy)benzoate (277mg) was treated overnight at rt with NaOH 1N (4.13 mL) in THF/MeOH (8mL, 2/1) (yield: 98%). LCMS (method B): 328.84 (M+H)⁺ at 1.33 min.

Step C:2-nitro-N-(3,4,5-trichlorophenyl)-5-((2-(trifluoromethyl)pyridin-3-yl)oxy)benzamide

2-nitro-5-((2-(trifluoromethyl) pyridin-3-yl) oxy) benzoic acid wastreated in a similar manner as step A of synthesis of example 1 (yield:45%). LCMS (method B): 505.7 (M+H)⁺ at 2.05 min.

Step D:2-amino-N-(3,4,5-trichlorophenyl)-5-((2-(trifluoromethyl)pyridine-3-yl)oxy)benzamide

2-nitro-N-(3,4,5-trichlorophenyl)-5-((2-(trifluoromethyl) pyridin-3-yl)oxy) benzamide was treated in a similar manner as step C Example 1(yield: 100%). LCMS (method B): 475.52 (M+H)⁺ at 2.21 min.

Step E:2-(methylsulfonamido)-N-(3,4,5-trichlorophenyl)-5-((2-(trifluoromethyl)pyridin-3-yl)oxy)benzamide

2-amino-N-(3,4,5-trichlorophenyl)-5-((2-(trifluoromethyl) pyridine-3-yl)oxy) benzamide was treated in a similar manner as step D of synthesis ofexample 1 (yield: 20%). LCMS (method C): 553.7 (M+H)⁺ at 2.07 min.

The substances named in the following Table 3 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of A¹ given in Table 3. The following physical dataare obtained according to the above-described HPLC/MS characterizationprocess.

TABLE 3 Ex. m/z: R_(t) [min] R_(t) [min] No. A¹ [M + H⁺] (Method)(Method) 3.1

556.7 2.09 (B) Solid 3.2

553.7 2.07 (B) Solid 3.3

551.7 3.95 (A) Foam 3.4

558.8 2.95 (C) Solid

Example 45-(4-chlorophenoxy)-2-(methylsulfonamido)-N-(4-(trifluoromethyl)oxazol-2-yl)benzamide(Ex 4.16 in Table 4) Step A: methyl 5-(4-chlorophenoxy)-2-nitrobenzoate

methyl 5-chloro-2-nitrobenzoate was treated in a similar manner as stepA of synthesis of example 3 (yield: 90%). LCMS (method B): 305.0 (M+H)⁺at 1.67 min.

Step B: methyl 2-amino-5-(4-chlorophenoxy) benzoate

methyl 5-(4-chlorophenoxy)-2-nitrobenzoate was treated in a similarmanner as step C Example 1 (yield: 100%). LCMS (method B): 277.82 (M+H)⁺at 1.88 min.

Step C: methyl 5-(4-chlorophenoxy)-2-(methylsulfonamido) benzoate

methyl 2-amino-5-(4-chlorophenoxy)benzoate was treated in a similarmanner as step D of synthesis of example 1 (yield: 95%). LCMS (methodB): 353.78 (M−H)⁻ at 1.84 min.

Step D: 5-(4-chlorophenoxy)-2-(methylsulfonamido) benzoic acid

methyl 5-(4-chlorophenoxy)-2-(methylsulfonamido)benzoate was saponifiedin a similar manner as step B of synthesis of example 4 (yield: 96%).LCMS (method B): 339.62 (M−H)⁻ at 1.61 min.

Step E: 5-(4-chlorophenoxy)-2-(methylsulfonamido)-N-(4-(trifluoromethyl)oxazol-2-yl)benzamide

5-(4-chlorophenoxy)-2-(methylsulfonamido) benzoic acid was treated in asimilar manner as step A of synthesis of example 1 (yield: 3%). LCMS(method B): 475.64 (M+H)⁺ at 1.70 min.

The substances named in the following Table 4 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of Y and R⁰ is given in Table 4. The followingphysical data are obtained according to the above-described HPLC/MScharacterization process (Method B).

TABLE 4 Ex. m/z: R_(t) [min] R_(t) [min] No. Y R⁰ [M + H⁺] (Method)(Method B) 4.1

H 503.7 1.94 Powder 4.2

H 447.7 1.99 Solid 4.3

H 482.6 1.94 Solid 4.4

H 495.6 1.76 Solid 4.5

H 423.6 1.69 Solid 4.6

H 468.6 1.79 Powder 4.7

H 492.7 1.83 Solid 4.8

H 487.6 1.99 Solid 4.9

H 509.7 1.95 Solid 4.10

H 608.6 1.85 Solid 4.11

H 508.6 2.32 Solid 4.12

H  563.6. 2.00 Solid 4.13

H 540.5 2.05 Solid 4.14

H 571.7 2.20 Solid 4.15

H 437.7 1.67 Solid 4.16

H 475.6 1.70 Oil 4.17

H 417.8 1.45 Oil 4.18

H 447.7 2.20 Oil 4.19

H 465.7 1.47 Oil 4.20

H 451.7 1.71 Oil 4.21

H 485.8 1.90 Oil 4.22

H 431.7 1.25 Powder 4.23

H 496.9 2.06 Foam 4.24

H 541.7 2.07 Solid 4.25

H 543.8 2.09 Solid 4.26

H 472.7 1.62 Solid 4.27

H 455.8 1.71 Solid 4.28

H 467.8 1.73 Solid 4.29

H 475.8 1.51 Solid 4.30

H 500.8 1.77 Solid 4.31

H 567.6 2.08 Solid 4.32

H 510.7 1.78 Solid 4.33

H 533.6 2.09 Oil 4.34

H 479.7 1.89 Powder 4.35

H 461.8 1.78 Oil 4.36

H 465.7 1.82 Oil 4.37

H 499.7 1.89 Oil 4.38

H 456.7 1.65 Oil 4.39

H 509.7 1.75 Oil 4.40

423.7 0.61 Powder 4.41

515.7 1.67 Foam 4.42

595.7 1.93 Powder 4.43

636.8 1.62 Solid 4.44

H 435.7 1.48 Solid 4.45

H 479.7 1.56 Solid 4.46

H 436.7 1.46 Solid 4.47

H 480.7 1.74 Oil 4.48

H 512.7 1.85 Solid 4.49

H 456.8 1.95 Resin 4.50

H 513.7 1.76 Solid 4.51

H 477.0 3.09 Foam 4.52

H 434.8 2.02 Oil 4.53

OH 481.7 3.27 Solid

Biological Examples

Gastro-Intestinal Larval Development Assay

Freshly harvested and cleaned nematode eggs are used to seed a suitablyformatted well plate containing the test substances to be evaluated forantiparasitic activity and media allowing the full development of eggsthrough to 3rd instar larvae. The plates are incubated for 6 days at 25°C. and 60% relative humidity. Egg-hatching and ensuing larvaldevelopment are recorded to identify a possible nematodicidal activity.Efficacy is expressed in percent reduced egg hatch, reduced developmentof L3, or paralysis & death of larvae at any stage. Compounds Nos. 1.4,1.10-1.12, 1.14, 1.16-1.21, 1.23, 1.25-1.26, 1.29-1.33, 2.1, 2.22, 2.28,2.42-2.43, 3.1-3.2, 4.1, 4.3-4.8, 4.19-4.24, 4.28, 4.32, 4.34,4.36-4.37, 4.39, 4.42-4.43 and 4.51 reached ≥60% efficacy at 10 ppm, andare therefore considered active.

Dirofilaria immitis Microfilaria Assay

Freshly harvested and cleaned Dirofilaria immitis microfilariae areprepared from blood from donor animals dogs. The microfilariae are thendistributed in formatted microplates containing the test substances tobe evaluated for antiparasitic activity. The plates are incubated for 48hours at 25° C. and 60% relative humidity (RH). Motility ofmicrofilariae is then recorded to determine efficacy. Efficacy isexpressed in percent reduced motility as compared to the control andstandards. Compounds Nos. 1.2-1.4 and 1.6 to 1.33, 2.1-2.20, 2.22-2.44,2.46, 3.1-3.4, 4.1-4.10, 4.12-4.16, 4.17-4.18, 4.21-4.29, 4.31-4.39,4.42 and 4.46-4.52 showed an efficacy above 50% at 10 ppm, and aretherefore considered active.

Acanthocheilonema viteae in Gerbil

Gerbils are artificially infected with 80 L3 larvae of A. viteae bysubcutaneous injection. Treatment by gavage with the formulated testcompounds occurs consecutively day 5 to day 9 after infection.Eighty-four days after infection, gerbils are bled for countingcirculating microfilariae, using a Fuchs-Rosenthal counting chamber andmicroscope. Only test groups with an average of circulatingmicrofilariae at least 50% lower than in the placebo treated group arefully dissected to recover adult worms. Efficacy is expressed as a %reduction in worm numbers in comparison with the placebo treated group,using the Abbot's formula. Compound No. 1.6-1.8, 1.17, 1.25, 1.30, 1.32,2.24, 4.13, 4.24 showed an efficacy above 80% at 10 mg/kg.

Adult Liver Fluke—In Vitro Assay

Freshly harvested adult Fasciola hepatica from cattle or sheep liverswere distributed in 12-well plates (1 fluke per well) with 4 mL of RPMIcomplete medium and kept in an incubator at 37° C. for approximately 12hours. After renewal of the medium, the viability of the flukes isdetermined by video-registration of the movement of the individualflukes (pre-value). Test compounds are added at a concentration of 100μg/mL and the movements of the flukes are measured after 6 and 24 hours.Efficacy is expressed as percent reduced movement based on the pre-valueand the untreated control. In this test the following examples showedmore than >90% efficacy after 6 h and >95% after 24 h are considered aspositive: 2.2, 4.13.

We claim:
 1. A compound of formula

or a salt or an enantiomer thereof, wherein n is 1; A is a phenylradical which is substituted by chlorine, fluorine or CF₃; R² is H or—S(O₂)-T; T is C₁-C₆-alkyl which is unsubstituted or substituted byhalogen, trimethylsilyl, C₃-C₆-cycloalkyl, carboxyl orC₁-C₄-alkoxycarbonyl; C₃-C₆-cycloalkyl; C₆-C₁₂-bicarbocyclyl; phenylwhich is unsubstituted or substituted by halogen, cyano, nitro,C₁-C₄-alkyl, C₁-C₄-haloalkyl or C₁-C₄-alkoxy; a 5- or 6 memberedheteroaromatic radical, which is further unsubstituted or substituted byhalogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl or C₁-C₄-alkoxy; 5-or 6-membered heterocycloalkyl having from 1 to 3 same or differentheteroatoms selected from the group consisting of N, O, S and S(O₂),which is further unsubstituted or substituted by C₁-C₄-alkyl,C₁-C₂-alkoxycarbonyl or benzyloxycarbonyl; a group

amino; or N-mono- or N,N-di-C₁-C₄-alkylamino; R³ is C₁-C₄-alkyl,unsubstituted or halogen-, C₁-C₄-alkyl- or C₁-C₄-haloalkyl-substitutedphenyl, unsubstituted or halogen-, C₁-C₄-alkyl- orC₁-C₄-haloalkyl-substituted pyridyl, C₁-C₄-alkoxycarbonyl-methyl ormorpholin-4-yl-carbonylmethyl; R⁰ is H or hydroxy; and Y is (i) phenylor a phenylamino, which is substituted by one or more same or differentradicals selected from the group consisting of halogen; C₁-C₂-alkyl;C₁-C₃-haloalkyl; C₁-C₂-alkoxy; C₁-C₃-haloalkoxy; C₁-C₂-haloalkylthio;SF₅; cyano; nitro; hydroxy; or methylsulfonylamino; or is (ii) 5- or 6membered heteroaryl or heteroarylamino, which is each furtherunsubstituted or substituted by halogen, cyano, nitro, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl, C₂-C₄-alkanoyl, orphenyl or phenylsulfonyl which is each unsubstituted or substituted byhalogen, cyano, nitro, methyl or methoxy; or is (iii) benzoyl or 5- or 6membered heteroarylcarbonyl, which is each further unsubstituted orsubstituted by halogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl, C₂-C₄-alkanoyl or phenyl; or is (iv)a C₆-C₁₂-bicarbocyclic radical; or is a (v) a hetero-bicyclic ringradical comprising a total of 8 to 10 ring members, from which 1 to 5members are same or different heteroatoms selected from the groupconsisting of B, N, O and S, and from which 0 to 2 members are a group—C(O)—, which bicyclic ring radical is further unsubstituted orsubstituted by halogen, cyano, hydroxyl, C₁-C₄-alkoxy, C₁-C₄-alkyl orC₁-C₄-haloalkyl; or is (vi) a radical —H₂C—C(O)—NH—R⁴, wherein R⁴ isC₁-C₄-haloalkyl, C₂-C₃-alkynyl or cyano-C₁-C₄-alkyl; or R⁰ and Ytogether with the N-atom to which they are attached, form a piperidinylor piperazinyl radical which is substituted by C₁-C₄-alkyl,C₁-C₄-alkoxy, unsubstituted or halogen-, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-,amino- and/or C₁-C₄-alkoxy-substituted phenyl or benzoylamino, orunsubstituted or C₁-C₄-alkyl-, C₁-C₄-haloalkyl-, C₃-C₆-cycloalkyl- orhalogen-substituted pyridyl or pyrimidinyl; subject to the proviso thatat least one of A and Y must not be a phenyl radical if T is CH₃.
 2. Acompound according to claim 1, wherein A is phenyl which ismono-substituted by chlorine, fluorine or CF₃, Y is phenyl which issubstituted by 2 or 3 same or different radicals selected from halogenor CF₃, and T is C₂-C₄-alkyl, which is unsubstituted or substituted byhalogen, cyclopropyl, cyclohexyl, trimethylsilyl, carboxy orC₁-C₂-alkoxycarbonyl; cyclopropyl or cyclohexyl; the radical of (+)- or(−)-camphor; phenyl which is unsubstituted or substituted by fluorine,chlorine, methyl, methoxy, CF₃ or nitro; or pyridyl, thienyl orpyrimidinyl; piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl or thiomorpholin-4-yl-1,1-dioxide, which is eachunsubstituted or substituted by methyl.
 3. A compound according to claim1 of formula

wherein A is phenyl which is substituted as defined in claim 1; R⁰ is Hor hydroxyl; and Y″ is (i) 5- or 6 membered heteroaryl orheteroarylamino, which is each further unsubstituted or substituted byhalogen, cyano, nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-alkoxycarbonyl, C₁-C₄-alkanoyl or phenyl or phenylsulfonyl whichis each unsubstituted or substituted by halogen, cyano, nitro, methyl ormethoxy; or is (ii) benzoyl or 5- or 6 membered heteroarylcarbonyl,which is each further unsubstituted or substituted by halogen, cyano,nitro, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxycarbonyl,C₁-C₄-alkanoyl or phenyl; or is (iii) a C₆-C₁₂-bicarbocyclic radical; oris a (iv) a hetero-bicyclic ring radical comprising a total of 8 to 10ring members, from which 1 to 5 members are same or differentheteroatoms selected from the group consisting of B, N, O and S, andfrom which 0 to 2 are a group —C(O)—, which bicyclic ring radical isfurther unsubstituted or substituted by halogen, cyano, hydroxyl,C₁-C₄-alkoxy, C₁-C₄-alkyl or C₁-C₄-haloalkyl; or is (v) a radical—H₂C—C(O)—NH—R⁴, wherein R⁴ is C₁-C₄-haloalkyl, C₂-C₃-alkynyl orcyano-C₁-C₄-alkyl; or R⁰ and Y together with the N-atom to which theyare attached, form a piperidinyl or piperazinyl radical which issubstituted by C₁-C₄-alkyl, C₁-C₄-alkoxy, unsubstituted or halogen-,C₁-C₄-alkyl-, halo-C₁-C₄-alkyl-, amino- and/or C₁-C₄-alkoxy-substitutedphenyl or benzoylamino, or unsubstituted or C₁-C₄-alkyl-,C₁-C₄-haloalkyl-, C₃-C₆-cycloalkyl- or halogen-substituted pyridyl orpyrimidinyl.
 4. A compound according to claim 3, wherein A is phenylwhich is mono-substituted by chlorine, fluorine or CF₃; R⁰ is H, and Y″is (i) 2-, 3- or 4-pyridyl which is unsubstituted or substituted byhalogen, C₁-C₄-alkyl or C₁-C₂-alkoxy; 2-thienyl which is unsubstitutedor substituted by C₁-C₂-alkyl, C₁-C₂-alkoxycarbonyl; 2-thiazolyl whichis unsubstituted or substituted by halogen, cyano, nitro, C₁-C₂-alkyl,C₁-C₂-haloalkyl, C₁-C₂-alkoxycarbonyl, or phenyl or phenylsulfonyl whichis in turn each unsubstituted or substituted by halogen, cyano, nitro ormethyl; 5-isothiazoyl which is unsubstituted or substituted by halogenor methyl; 2-oxazolyl, which is unsubstituted or substituted byC₁-C₂-alkyl or C₁-C₂-haloalkyl; or 1,3,4-thiadiazol-5-yl, which isunsubstituted or substituted by C₁-C₂-alkyl or C₁-C₂-haloalkyl; 2-, 3-or 4-pyridylamino, which is unsubstituted or substituted by halogen,C₁-C₄-alkyl or C₁-C₂-alkoxy; or (ii) benzoyl which is unsubstituted orsubstituted by halogen, or 2-, 3- or 4-pyridylcarbonyl which isunsubstituted or substituted by halogen or C₁-C₄-alkyl; or (iii) aradical

a radical

or indanyl; or (iv) benzothiazolyl, indolyl, quinolinyl,methylenedioxophenyl, benzooxaboronyl, triazolopyrimidinonyl orphthalhydrazidyl, which is each unsubstituted or substituted by halogen,C₁-C₄-alkyl, C₁-C₂-haloalkyl or hydroxy; or (v) a radical—H₂C—C(O)—NH—CH₂—C≡CH, —H₂C—C(O)—NH—CH₂—CN or —H₂C—C(O)—NH—CH₂—CF₃; orR⁰ and Y together with the N-atom to which they are attached, form apiperidinyl or piperazinyl radical, which is substituted by methyl;methoxy; halogen-, amino-, methoxy- or trifluoromethyl-substitutedphenyl or benzoylamino; or halogen-, trifluoromethyl- and/orcyclopropyl-substituted pyridyl or pyrimidinyl.
 5. A composition for thecontrol of parasites, which contains as an active ingredient at leastone compound of formula (I) according to claim 1, in addition tocarriers and/or dispersants.
 6. A method of controlling endoparasites,on warm-blooded animals, which comprises administering to thewarm-blooded animals a veterinary effective amount of at least onecompound of formula (I) according to claim
 1. 7. A compound of theformula:

wherein (R)_(m) is H or 4-Cl; T is 4-CH₃-phenyl, phenyl,2-NO₂-4-CF₃-phenyl, 3-Cl-4-F-phenyl, 2-CF₃-4-F-phenyl, 4-CF₃-phenyl,3,4-dimethoxyphenyl, 4-nitrophenyl, 4-chlorophenyl, 3,5-di-Cl-phenyl,4-methoxyphenyl, 2-chloro-phenyl, 3-chloro-phenyl, 3-pyridyl,3-methoxyphenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl,2-methoxyphenyl, 2,4-dichlorophenyl, 2-NO₂-4-OCH₃-phenyl,2,4-dimethoxyphenyl, ethyl, —CH₂CF₃, —CH₂CH₂CF₃, n-propyl, n-butyl,iso-butyl, —CH₂CH₂Si(CH₃)₃, cyclopropyl, cyclohexyl,1-(benzyloxycarbonyl)-piperazin-4-yl, isopropyl, cyclohexylmethyl,(1R)-(−-campher, —CH₂C(O)OC₂H₅, —CH₂C(O)OCH₃, —CH₂C(O)OH,(1S)-(+)-campher, tetrahydro-2H-pyran-4-yl, —N(CH₃)₂,1-methylpiperazin-4-yl, —CH₂—Cl,

and R² is H or —SO₂CH₂Cl.
 8. A compound according to claim 7, wherein(R)_(m) is 4-Cl and R² is H.
 9. A compound according to claim 7, havingthe formula:


10. A composition for the control of parasites, which contains as anactive ingredient the compound according to claim 7, in addition tocarriers and/or dispersants.
 11. A method of controlling endoparasites,on warm-blooded animals, which comprises administering to thewarm-blooded animals a veterinary effective amount of the compoundaccording to claim
 7. 12. A compound of the formula:

wherein R⁰ is H or hydroxy; and Y is

or R⁰ and Y together with the N-atom to which they are attached, form


13. A compound according to claim 12, wherein R⁰ is H.
 14. A compositionfor the control of parasites, which contains as an active ingredient thecompound according to claim 12, in addition to carriers and/ordispersants.
 15. A method of controlling endoparasites, on warm-bloodedanimals, which comprises administering to the warm-blooded animals aveterinary effective amount of the compound according to claim 12.